Knickle L C, Philpot R M, Bend J R
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
J Pharmacol Exp Ther. 1994 Jul;270(1):377-85.
1-Aminobenzotriazole (ABT) and its N-benzyl-1-aminobenzotriazole (BBT) and N-alpha-methylbenzyl (alpha-MB) derivatives were compared as isozyme-selective, lung-selective (vs. liver) mechanism-based inhibitors of cytochrome P-450 (P450) in noninduced, beta-naphthoflavone-induced and phenobarbital-induced guinea pigs 4 hr after i.v. administration. Isozyme-selective monooxygenase activities for lung P450 1A1, 2B4 and 4B1 orthologues (7-ethoxyresorufin O-deethylation for guinea pig P450 1A1, 7-pentoxyresorufin O-depentylation for P450 2Bx and 4-aminobiphenyl N-hydroxylation for P450 4Bx, respectively) were determined in pulmonary and hepatic microsomes. BBT and alpha-MB inactivated pulmonary P450 in an isozyme-selective manner; in non- and phenobarbital-induced animals the order of inactivation was 2Bx > 1A1 >>> 4Bx. In beta-naphthoflavone-induced animals, alpha-MB specifically inhibited 2Bx in the lung (>90% inactivation at 0.075 mumol/kg, whereas a 100-fold higher dose did not inhibit 4Bx or 1A1). BBT and alpha-MB also were highly selective for the inactivation of pulmonary vs. hepatic P450. In each case at least one of the doses administered caused marked inactivation of pulmonary 2Bx (>80% with alpha-MB and 50-70% with BBT) without inhibiting the hepatic monooxygenase activities. In contrast, ABT displayed little isozyme-selectively and little tissue-selectivity. The differences in tissue-selectivity of the inhibitors are due to BBT and alpha-MB being much more potent (100- to 1000-fold) inactivators of pulmonary P450 2Bx than ABT consistent with BBT and alpha-MB, but not ABT, serving as substrates for the lipophilic aromatic amine uptake system in the lung. In summary, BBT and alpha-MB, at appropriate doses, are isozyme-selective/specific (P450 2Bx), lung-specific inhibitors of P450 in guinea pig in vivo.
将1-氨基苯并三唑（ABT）及其N-苄基-1-氨基苯并三唑（BBT）和N-α-甲基苄基（α-MB）衍生物作为基于同工酶选择性、肺选择性（相对于肝脏）的细胞色素P-450（P450）的基于机制的抑制剂，在静脉注射给药4小时后的未诱导、β-萘黄酮诱导和苯巴比妥诱导的豚鼠中进行比较。测定肺P450 1A1、2B4和4B1直系同源物的同工酶选择性单加氧酶活性（分别为豚鼠P450 1A1的7-乙氧基试卤灵O-脱乙基化、P450 2Bx的7-戊氧基试卤灵O-脱戊基化和P450 4Bx的4-氨基联苯N-羟基化）在肺和肝微粒体中的情况。BBT和α-MB以同工酶选择性方式使肺P450失活；在未诱导和苯巴比妥诱导的动物中，失活顺序为2Bx＞1A1＞＞＞4Bx。在β-萘黄酮诱导的动物中，α-MB特异性抑制肺中的2Bx（在0.075μmol/kg时失活＞90%，而高100倍的剂量不抑制4Bx或1A1）。BBT和α-MB对肺P450相对于肝P450的失活也具有高度选择性。在每种情况下，至少一种给药剂量导致肺2Bx明显失活（α-MB时＞80%，BBT时50 - 70%），而不抑制肝单加氧酶活性。相比之下，ABT几乎没有同工酶选择性和组织选择性。抑制剂在组织选择性上的差异是由于BBT和α-MB作为肺P450 2Bx的失活剂比ABT有效得多（100至1000倍），这与BBT和α-MB但不是ABT作为肺中亲脂性芳香胺摄取系统的底物一致。总之，在适当剂量下，BBT和α-MB是豚鼠体内P450的同工酶选择性/特异性（P450 2Bx）、肺特异性抑制剂。
